1. Field of the Invention
This invention relates to a novel optically activate substance, preferably usable as an intermediate for preparing HMG-CoA reductase inhibitor, known as a remedy for high cholesterol blood disease, and a process for producing the same.
2. Description of the Related Art
The HMG-CoA reductase inhibitor has been noted as a remedy for high cholesterol blood disease, and a number of its homologues have been synthesized and active research of its pharmaceutical activity has been carried out. As one area of researches, a pyrrole derivative of the following formula (7) has been disclosed in U.S. Pat. No. 4,681,893 (Bruce D. Roth et al): ##STR2##
Further, an effective process for producing the compound of the formula ( 7 ) has been disclosed in U.S. Pat. No. 5,003,080 (Donald E Butler et al). The literature of the prior art shows that when the following compounds of the formulas (8) and (9) are treated with 10% hydrochloric acid, the compound of the formula (7) can be easily prepared: ##STR3## Further, it is also shown that the other preparation fragment (9) is prepared by catalytically reducing the following nitrile compound (10) at 0.degree. to 70.degree. C.: ##STR4##
However, the process for producing the nitrile compound (10), disclosed in the above literature of the prior art is commercially inferior. Namely, the disclosed process for producing the nitrile compound (10) consists of the following steps:
Firstly, an alkyllithium, iodine and CO.sub.2 in this order are reacted with 1,6-heptadiene-4-ol (11) to generate an iodide (12) in the reaction system, followed by treating it with an alkali or alkaline earth hydroxide or carbonate to prepare an epoxide (13). ##STR5##
An alkali metal cyanide is reacted with the epoxide to open the oxirane ring, followed by ketalization to obtain (14), oxidizing it with ozone at -20.degree. to -78.degree. C. to obtain an aldehyde (15), further oxidizing it with Jones reagent to obtain a carboxylic acid (16), and esterifying it with an alkyl halide in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) to obtain (17). ##STR6##
However, the above processes have the following commercial disadvantages:
1. In the preparation of (12), it is necessary to use an alkyllithium which is difficult to deal with. PA1 2. In the preparation of (15), it is necessary to carry out ozone oxidation at low temperatures (-20.degree. to -78.degree. C.). PA1 3. In the preparation of (16), it is necessary to use Jones reagent containing harmful chromic acid. PA1 1. An optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-substituted pentane expressed by the formula ##STR8## wherein R.sup.l represents a halogen atom or cyano group and R.sup.2 represents an alkyl group of 1 to 6 carbon atoms. PA1 2. A process for producing an optically active erythro-1-alkanoyloxy-2 ,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentane which process comprises reacting an ester with meso-1,2,4,5-pentanetetraol expressed by the formula ##STR9## in the presence of a lipase to prepare a meso-1,5-alkanoyloxy-2,4-dihydroxypentane expressed by the formula ##STR10## wherein R.sup.3 represents an alkyl group of 1 to 10 carbon atoms; ketalizing the compound ( 3 ) to prepare a meso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentane expressed by the formula ##STR11## dealkanolizing the compound (4) to prepare meso-2,4-O-isopropylidene-l,2,4,5-pentane tetraol expressed by the formula ##STR12## reacting an ester with (5) in the presence of a lipase to prepare an optically active erythro-l,alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressed by the formula ##STR13## wherein R.sup.2 represents an alkyl group of 1 to 10 carbon atoms, and halogenating it, to prepare an optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogeopentane expressed by the formula ##STR14## wherein R.sup.1 represents a halogen atom and R.sup.2 represents an alkyl group of 1 to 6 carbon atoms. PA1 3. A process for producing an optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane, which process comprises reacting an ester with meso-1,2,4,5-pentanetetraol expressed by the formula ##STR15## in the presence of a lipase to prepare a meso-1,5-alkanoyloxy-2,4-dihydroxypentane expressed by the formula ##STR16## wherein R.sup.3 represents an alkyl group of 1 to 10 carbon atoms; ketalizing the compound (3) to prepare a meso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentane expressed by the formula ##STR17## dealkanolizing the compound (4) to prepare meso-2,4-O-isopropylidene-l,2,4,5-pentane tetraol expressed by the formula ##STR18## reacting an ester with (5) in the presence of a lipase to prepare an optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,5-pentanetriol expressed by the formula ##STR19## wherein R.sup.2 represents an alkyl group of 1 to 10 carbon atoms, halogenating it, to prepare an optically active alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentane expressed by the formula ##STR20## wherein R.sup.1 represents a halogen atom and R.sup.2 represents an alkyl group of 1 to 6 carbon atoms, and cyanizing it, to prepare an optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane expressed by the formula ##STR21## p10 wherein R.sup.1 represents a cyano group and R.sup.2 represents an alkyl .group of i to 6 carbon atoms. PA1 4. A process for producing an optically active erythro-1- alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressed by the formula ##STR22## wherein R.sup.2 represents an alkyl group of 1 to 6 carbon atoms, which process comprises reacting an ester with meso-2,4-O-isopropylidene-l,2,4,5-pentanetetraol expressed by the formula ##STR23## in the presence of a lipase. 5. A process for producing a meso-1,5-dialkanoyloxy-2,4-dihydroxypentane expressed by the formula ##STR24## wherein R.sup.3 represents an alkyl group of 1 to 10 carbon atoms, which process comprises reacting an ester with meso-1,2,4,5-pentanetetraol expressed by the formula ##STR25## in the presence of a lipase. 6. A process for producing an optically active erythro-3,5-O-isopropylidene-3,5,6-trihydroxy-hexanoate, which process comprises reacting an ester with meso-1,2,4,5-pentanetetraol expressed by the formula ##STR26## in the presence of a lipase to prepare a meso-1,5-alkanoyloxy-2,4-dihydroxypentane expressed by the formula ##STR27## wherein R.sup.3 represents an alkyl group of 1 to 10 carbon atoms; ketalizing the compound (3) to prepare a meso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentane expressed by the formula ##STR28## dealkanolizing the compound (4) to prepare meso-2,4-O-isopropylidene-1,2,4,5-pentane tetraol expressed by the formula ##STR29## reacting an ester with (5) in the presence of a lipase to prepare an optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressed by the formula ##STR30## wherein R.sup.2 represents an alkyl group of 1 to 10 carbon atoms, halogenating it, to prepare an optically active alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentane expressed by the formula ##STR31## wherein R.sup.1 represents a halogen atom and R.sup.2 represents an alkyl group of 1 to 6 carbon atoms, and cyanizing it, to prepare an optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane expressed by the formula ##STR32## wherein R.sup.1 represents a cyano group and R.sup.2 represents an alkyl group of 1 to 6 carbon atoms, and converting the cyano group into an alkoxycarbonyl group, to prepare an optically active erythro-3,5-O-isopropylidene-3,5,6-Trihydroxyhexanoate expressed by the formula ##STR33## wherein R.sup.4 represents an alkyl group of 1 to 6 carbon atoms.
Furthermore, according to this preparation route, while it is possible to separately prepare an erythroform substance and a threo-form substance, it is impossible to prepare an optically active substance. Thus, the final product prepared through the preparation route is a racemic substance. A pyrrole derivative having a physiological activity as HMG-CoA reductase inhibitor is only 2R-transform substance expressed by the formula (7), and optical isomers have no activity.
The above U.S. Pat. No. 5,003,080 also discloses preparation of an optically active substance. Namely, the above optically active nitrile compound (10) is prepared through the following route:
A carboxylic acid (19) derived from isoascorbic acid (18) according to a known method has one more carbon atom increased, using carbonyldiimidazole and a half ester of malonic acid, to prepare (20), followed by removing the protective group to obtain an alcohol (21).
This alcohol is stereoselectively reduced with triethylborane or methoxydiethylborane and then with sodium borohydride, at -78.degree. to -110.degree. C. preferably -100.degree. C., to obtain a diol (22), followed by protecting the hydroxyl groups with acetonide to obtain the above nitrile compound ( 10 ) . ##STR7##
However, the above process cannot be regarded as a commercially advantageous process, since conversions of the isoascorbic acid (18) into the carboxylic acid (19) requires a number of steps and reduction of the alcohol (21) requires an extremely low temperature (because no steroselectivity is exhibited at high temperatures).
Thus, a novel optically active compound equivalent to optically active nitrile compound (10) or easily convertible into (10), and a process for producing a novel optically active compound easily convertible into (10) under mild reaction conditions and commercially advantageously, have been required.
The present inventors have made extensive research in order to solve the above-mentioned problems, and as a result, have found a novel and useful optically active compound, i.e. an optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-substituted pentane (1) of the present invention, equivalent to or easily converted into an optically active nitrile compound (10) as a raw material for preparing a pyrrole derivative (7) which is one of HMG-CoA reductase inhibitors, and a suitable and simple process for producing the compound of the present invention (1); thus the present invention has been completed.
As apparent from the foregoing, the object of the present invention is to provide the above-mentioned novel compound and a process for producing the same.